Stony Brook University School of Medicine, New York
Our research program focuses on examining the role of adenine-monophosphate protein kinase (AMPK) in modulating the fate of renal tubular cells (RTCs) in culture when exposed to acute injury, and in altering the severity of renal dysfunction following acute kidney injury (AKI) in vivo. AMPK is a serine/threonine kinase that is activated by very small decreases in cell energy charge. AMPK therefore acts as a sensitive “gauge” of cell energy charge.
When activated by ATP depletion, AMPK phosphorylates a number of downstream kinases, enzymes and transcription factors. These many downstream effects of AMPK have complex effects on glucose, protein and fat metabolism, on cell proliferation and on apoptosis. The metabolic functions of AMPK are currently an area of intensive research. One well established effect of AMPK activation is the conservation of cell energy stores, mediated by inhibiting anabolic processes while stimulating energy producing pathways.
We have published evidence demonstrating, that AMPK activation reduces apoptosis of RTCs exposed to metabolic stress in vitro, and ameliorates the severity of AKI in mice in vivo. We have also reported, that preconditioning mice with pharmacologic activators of AMPK substantially enhances the ameliorative effect of AMPK in AKI in mice. We are currently doing studies to examine the mechanisms responsible for these effects of pharmacologic AMPK activators. Some of our findings so far suggest that the effects of AMPK activation in AKI are mediated, in part, by the stimulation glycolysis and the activation of Akt (a ubiquitous anti-apoptotic kinase).
There is substantial evidence in the literature, that pharmacologic activators of AMPK have beneficial effects in a number of mouse models of diseases common in humans. These include diabetes, the metabolic syndrome and cancer. This information has led to considerable interest by investigators, in the potential utility of these activators as novel forms of treatment in humans for these diseases. However, the pharmacologic activators of AMPK that have been used for these studies, lack sufficient potency and specificity to be useful as therapeutic agents in humans.
However, recent research has led to the development of a few novel agents that appear to be highly potent and specific activators of AMPK. We have begun studies to examine the effect of these new AMPK activators on the course of ischemic AKI. We have published data showing that one of these this novel AMPK activator markedly protects mice from renal injury and dysfunction induced by ischemic injury. Our long term goal, is to identify highly specific activators of AMPK that may prove effective and safe therapeutic agents, in preventing or ameliorating AKI in humans.